Crosslinked chitosan nanoparticle formulations for delivery from pressurized metered dose inhalers

Crosslinked chitosan nanoparticles, prepared using ionic gelation, have been successfully formulated into pressurized metered dose inhalers (pMDIs) with potential for deep lung delivery of therapeutic agents. Nanoparticles were prepared from crosslinked chitosan alone and incorporating PEG 600, PEG 1000 and PEG 5000 for dispersion in aerosol propellant, hydrofuoroalkane (HFA) 227. Spherical, smooth-surfaced, cationic particles of mean size less than 230 nm were produced. Nanoparticles were positively charged and non-aggregated at the pH of the airways. Crosslinked chitosan-PEG 1000 nanoparticles demonstrated greatest dispersibility and physical stability in HFA-227, whereas other formulations readily either creamed or sedimented. Following actuation from pMDIs, the fine particle fraction (FPF) for crosslinked chitosan-PEG 1000 nanoparticles, determined using a next generation impactor, was 34.0±1.4% with a mass median aerodynamic diameter of 4.92±0.3 μm. The FPFs of crosslinked chitosan, crosslinked chitosan-PEG 600 and crosslinked chitosan-PEG 5000 nanoparticles were 5.7±0.9%, 11.8±2.7% and 17.0±2.1%, respectively. These results indicate that crosslinked chitosan-PEG 1000-based nanoparticles are promising candidates for delivering therapeutic agents, particularly biopharmaceuticals, using pMDIs.